CN102212013A - Polyamine compound and preparation method and application thereof - Google Patents
Polyamine compound and preparation method and application thereof Download PDFInfo
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- CN102212013A CN102212013A CN2011100793917A CN201110079391A CN102212013A CN 102212013 A CN102212013 A CN 102212013A CN 2011100793917 A CN2011100793917 A CN 2011100793917A CN 201110079391 A CN201110079391 A CN 201110079391A CN 102212013 A CN102212013 A CN 102212013A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/20—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic unsaturated carbon skeleton
- C07C211/22—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic unsaturated carbon skeleton containing at least two amino groups bound to the carbon skeleton
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Abstract
The invention discloses a polyamine compound and a preparation method and application thereof. The invention discloses a novel trans-acroleic acid derivative, i.e., a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof. The compound shown as the formula (I) in the invention or the pharmaceutically acceptable salt thereof has the activity of selectively inhibiting tumor cells and low toxicity on organisms. The invention further discloses a preparation method of the compound shown as the formula (I). The preparation method is safe, simple and feasible. The compound shown as the formula (I) or the pharmaceutically acceptable salt thereof has a novel structure and high antineoplastic activity, fills up the blank in the field, can be used for preparing an antitumor medicament being used for selectively inhibiting tumor cells and having low toxicity on organisms, and has an important industrial development value and great contribution to the research of anti-cancer medicaments for human beings.
Description
Technical field
The present invention relates to a kind of polyamine compounds and its production and application.
Background technology
Tumour is the serious disease of harm humans health, and the preventing and controlling of tumour are the emphasis in medical research field always.At present, because the problems of bringing in the industrial development such as environmental pollution, the existent environment of people quality constantly descends, and causes the sickness rate of tumor disease and lethality rate constantly to rise.Radiotherapy, chemotherapy are the main means for the treatment of tumour at present.But chemotherapy, radiotherapy have reduced immunity of organisms having suppressed also to have suppressed Normocellular growth when cancer cells is grown, and cause new complication.The specifics of treatment tumor disease can not be satisfactory, and clinical used cytotoxic drug selectivity is not high at present, causes Normocellular pernicious killing and wounding limited its application.Therefore, the antitumor drug of seeking new, no wound, acellular toxic action becomes the important directions of international field of medicaments.
The present invention relates to a kind of new polyamine compounds, experimental results show that to have activity preferably through external, anti-tumor in vivo.
Disclosure of the Invention
The invention provides a kind of antineoplastic compound, is a kind of new polyamine derivative and pharmacologically acceptable salt thereof, is specially formula (I) compound or its pharmacy acceptable salt:
R＝-CH
2CF
3；-CH
2CH
2F；-CH
2Cl；-CH
2CH
2Cl；CH
2CH
2Br；-CF
3；-CH
2Br。
Wherein preferred: R=-CH
2CF
3(compound 6 as shown in Figure 1).
Described pharmacy acceptable salt can be inorganic salt and organic salt, example hydrochloric acid salt, phosphoric acid salt salt, vitriol, acetate, maleate, oxalate, malate etc.
Another object of the present invention provides the intermediate of synthetic compound 6, is respectively compound 3,4,5 as shown in Figure 1.
The synthetic route chart of Fig. 1 synthetic compound 6 and salt thereof (compound 1 as shown in the figure)
The present invention also provides a kind of method for preparing compound 6, and contained other compound of formula (I) can get by similar approach.Described formula (I) compound or its pharmacy acceptable salt can be applicable to preparation and prevent and/or treat in the tumour medicine.Described tumour specifically can be liver cancer or lung cancer.The described tumour medicine that prevents and/or treats can be any formulation, as injection liquid, lyophilized powder, oral tablet, capsule, dripping pill or granule.
The best mode that carries out an invention
Further illustrate its preparation method and antitumous effect with compound 6 below.All results with
Expression is organized a significant difference relatively with the t check.
Experimental technique among the following embodiment if no special instructions, is ordinary method.
Embodiment 1: the preparation of compound
(1) compound 2 is synthetic:
With (Z)-butylene glycol (8.80g, 0.10mol) and triethylamine (12.1g 0.12mol) is dissolved among the DCM of 50mL, slowly drip benzene sulfonyl chloride (25.2g down at 0 ℃, 0.11mol) DCM (50mL) solution, after dropwising, reaction solution moves on in the room temperature and to continue reaction 5 hours again, stopped reaction, obtain 22.3 after suction filtration, filtrate decompression remove and desolvate and digest compound 2, productive rate 90%, HNMR (400Hz, CDCl
3): 5.87 (m, 2H), (d, 2H, J=8.7Hz), (s, 6H).
(2) compound 3 is synthetic:
Ethyl cyanoacetate (22.62g, 0.20mol) be dissolved in the ethanol of 50mL, at room temperature drip trifluoro ethamine (10.9g, 0.11mol), after dropwising reaction system is moved on to 80 ℃ and reacted stopped reaction 3 hours down, obtain 15.3 after underpressure distillation removes and desolvates and digest compound 3, productive rate 92%, HNMR (400Hz, CDCl
3): 3.70 (m, 2H), 3.3 (s, 2H).
(3) compound 4 is synthetic
Digesting compound 3 with 15 is dissolved among the THF of 100mL, a spot of in batches adding sodium borohydride (13.7g, 0.36mol), Dropwise 5 0mL iodine (45.7g in ice bath, 0.18mol) THF solution, dropwise the afterreaction system and move on to 70 ℃ of reactions 5 hours, stopped reaction is cooled to room temperature, add 50mL water, dichloromethane extraction, organic phase obtain 9.8 gram products 4, productive rate 70% after removing solvent final vacuum drying.HNMR(400Hz，CDCl
3)：3.07(m，2H)，2.65(m，2H)，2.55(m，2H)，1.67(m，2H)。
(4) compound 5 is synthetic:
Digest compound 4 and triethylamine (12.8g with 9.0,0.17mol) be dissolved among the THF of 100mL, slow Dropwise 5 0mL methylsulfonyl chloride (13.9g in the ice bath, 0.12mol) THF solution, after dropwising, reaction system at room temperature continued to react 3 hours, stopped reaction, filter, filtrate obtains 14.9 gram product compounds 5, productive rate 83% after concentrating vacuum-drying.HNMR(400Hz，CDCl
3)：3.07(m，2H)，2.84(s，6H)，2.65(m，2H)，2.55(m，2H)，1.67(m，2H)。
(5) compound 6 is synthetic:
Digest compound 5 with 14 and be dissolved among the 20mL exsiccant DMF, in ice bath, add in batches NaH (1.30g, 0.054mol), stir after 30 minutes, slowly drip 30mL compound 2 (10.9g, THF solution 0.045mol), after dropwising, reaction system moves on to and continues under the room temperature to stir 8 hours, and stopped reaction is poured reaction solution in the frozen water of 200mL, dichloromethane extraction, organic phase underpressure distillation behind anhydrous sodium sulfate drying removes desolvates, and obtains 13.9 after the vacuum-drying and digests compound 6, productive rate 85%.HNMR(400Hz，CDCl
3)：5.75(m，2H)，3.21(m，4H)，3.07(m，4H)，2.60(m，4H)，2.51(m，4H)，1.60(m，4H)；MS?m/z：365.12
(6) compound 1 is synthetic:
Under the room temperature 13 anhydrous methanols that digest compound 6 usefulness 50mL are dissolved, slow Dropwise 5 0mL methanol hydrochloride solution (4M), at room temperature stirring after 12 hours underpressure distillation removes and desolvates, after adding 20mL water, dichloromethane extraction, anhydrous sodium sulfate drying, removing methanol hydrochloride solution (4M) back of the back adding 50mL that desolvates continues to stir 3 hours, with washed with dichloromethane (10mL * 3), obtain 16.6 after the vacuum-drying and digest compound 1, productive rate 91% after the removal of solvent under reduced pressure.HNMR(400Hz，CD
3OD)：5.76(m，2H)，3.18(m，4H)，3.03(m，4H)，2.61(m，4H)，2.52(m，4H)，1.62(m，4H)；MS?m/z：365.12
Embodiment 2: the anti-tumor activity of compound 6 (replacing compound 6 with code name Zonk088CT in the test)
(1) external inhibition test
Experiment material
Medicine and reagent: Zonk088CT, white powder is provided by Guangdong Zonk Drug R ﹠ D Limited.
The RPMI1640 substratum: GIBCO company produces.
New-born calf serum (super), Hangzhou Sijiqing Biological Engineering Material Co., Ltd..
Trypsinase, Sigma company produces.
Cell strain: human hepatoma cell strain SMMC-7721, human lung adenocarcinoma cell line A549, human glioma cell line U251, human stomach cancer cell line BGC-823 are all available from institute of Materia Medica,Chinese Academy of Medical Sciences pharmacological room.
Instrument: CO
2Incubator (Forma 3110, USA), Bechtop (Ha Dong joins BCN-1360B), (Bio-Rad 550 for microplate reader, USA), and inverted microscope (Nikon TE2000, Japan), Tissue Culture Flask (Costar, USA), and 96 porocyte culture plates (Costar, USA).
Experimental technique:
Medicine and reagent preparation: the RPMI1640 substratum adds one liter in water for one bag, adds 2 gram sodium bicarbonates, and 100,000 unit penicillin and 100mg Streptomycin sulphate are regulated pH value to 7.4, with 0.22 μ m degerming membrane filtration degerming.The 95ml substratum adds deactivation new-born calf serum 5ml and is complete culture solution.Trypsinase is made into 0.25% solution with the D-hanks damping fluid, and 4 ℃ of preservations are standby after the filtration sterilization.
Accurately take by weighing Zonk088CT 100mg, be added in the 1.5ml centrifuge tube of sterilization, add DMSO 1ml, be made into 100mg/ml stoste ,-20 ℃ of freezing preservations.Face with getting after the preceding thawing in right amount and be diluted to the respective concentration application with complete culture solution.
Cell cultures and going down to posterity: the equal adherent culture of all cells is in containing 10ml complete culture solution Tissue Culture Flask, in 37 ℃, 5%CO
2, full closing under the humidity cultivate.Wash twice with sterilization D-hanks liquid after at the bottom of cell covers with bottle, add 0.25% trypsin digestion and cell 2 minutes, outwell trypsinase, after treating that the jog cell can come off fully, add complete nutrient solution 30ml after, dispel cell with transfer pipet, be sub-packed in 3 new Tissue Culture Flasks, continue to cultivate.
Drug treating: get one bottle in the cell that just covered with, collecting cell behind the tryptic digestion with transfer pipet piping and druming evenly, is got two cell suspension trypan blues dyeing, in microscopically living cell counting number, adjusts cell number to 1 * 10 with complete culture solution
5Individual cells/ml.Every hole adds 100 μ l cell suspensions in 96 porocyte culture plates, and culture plate is placed CO
2Cultivated 12 hours in the incubator, in every hole, add the complete culture solution that 100 μ l contain different concns Zonk088CT after taking out culture plate, make the medicine final concentration be respectively 80.0,60.0,45.0,33.8 and 25.3 μ g/ml, each concentration is established 4 parallel holes, other establishes 4 porocytes and adds not the pastille complete culture solution and make negative control hole, 4 porocytes add the complete culture solution that contains vincristine(VCR) and make positive control, and the vincristine(VCR) final concentration is 5 μ g/ml.Add behind the medicine culture plate mixing that on the microwell plate vibrator, vibrates, place CO
2Continue in the incubator to cultivate 48 hours.Take out culture plate, every hole adds the MTT liquid of 10 μ l 5mg/ml, the vibration mixing, continue to cultivate 4 hours, discard original fluid, add DMSO 150 μ l in every hole, fully vibration is with the crystallization of dissolving bluish voilet, on Bio-Rad 550 microplate reader, measure the photoabsorption in each hole, measure wavelength 570nm, reference wavelength 630nm.
Calculate the inhibiting rate of medicine on cell proliferation according to each hole OD value:
Inhibiting rate according to the logarithm correspondence of drug level is done straight-line regression, obtains straight-line equation, calculates inhibiting rate and is the 503nhibiting concentration (IC of Zonk088CT to tumour cell at the drug level of 50% o'clock correspondence
50).
Measure the IC of every strain cell down in above-mentioned similarity condition
50, the continuous triplicate of every strain cell experiment.
Experimental result:
Table 1 Zonk088CT is to half 503nhibiting concentration (IC of different tumor cell lines
50, μ g/ml)
(2) inhibition test in the body
Experiment material:
Medicine and reagent: ZONK088CT, white powder is provided by Guangdong Zonk Drug R ﹠ D Limited.
Cyclophosphamide for injection, Hengrui Medicine Co., Ltd., Jiangsu Prov.'s product.
Animal and knurl strain: SPF level Kunming kind small white mouse, body weight 18～22g is provided by Shandong Luye Pharmaceutical Co., Ltd.'s animal center, conformity certification number: SYXK (Shandong) 20030020.SPF level C57BL/6 inbred mouse, body weight 18～22g, available from Institute of Experimental Animals, Chinese Academy of Medical Sciences, conformity certification number: SCXK11-00-0006.Mouse H22 liver cancer, B16 melanoma are all drawn from institute of materia medica, Chinese Academy of Medical Sciences Beijing.
Instrument: CO
2Incubator (Forma 3110, USA), and Bechtop (BCN-1360, east, Harbin connection), inverted microscope (Nikon).
Experiment 1:H22 liver cancer
H22 liver cancer is got the ascites preservation of going down to posterity after Kunming mouse abdominal cavity inoculation.Get the H22 liver cancer tumor-bearing mice that ascites went down to posterity the 10th, take off cervical vertebra and put to death mouse, the sterilization skin of abdomen is drawn oyster white ascites with asepsis injector, and adjusting tumour cell concentration with injection physiological saline is 1 * 107 cell/ml.With cotton ball soaked in alcohol sterilization Kunming mouse right side armpit skin, in the above-mentioned tumor cell suspension 0.2ml of subcutaneous vaccination, the conventional raising.
Grouping and administration: 50 of tumor-bearing mices, be divided into 5 groups at random by body weight, 10 every group, be respectively model group, endoxan group, ZONK088CT10,30,90mg/kg group.Each organizes mouse by dosage shown in the table 2 and mode administration, and the endoxan group only gives endoxan one time in the abdominal cavity in lotus knurl second day, and ZONK088CT organizes equal every day of tail intravenously administrable 1 time, continuous 10 days.Administration volume 20ml/kg body weight.After the last administration 24 hours, take off cervical vertebra and put to death mouse, weigh, strip tumor tissue and weigh, calculate tumour inhibiting rate.
The result with
Expression is organized a significant difference relatively with the t check.
The result shows, the ZONK088CT continuous intravenous injection of 30mg/kg 10 days is inhibited to the growth of mice transplanted tumor H22 liver cancer.
Table 2 ZONK088CT is to the restraining effect of mouse H22 liver cancer growth
Compare with model group:
*, P＜0.05;
*, P＜0.01.
Experiment 2:B16 melanoma
The B16 melanoma is in the C57BL/6 mouse oxter subcutaneous vaccination preservation of going down to posterity.The B16 melanoma tumor-bearing mice of selecting tumor growth oxter good, that do not have necrosis or liquefaction to go down to posterity and preserve, take off cervical vertebra and put to death mouse, after the 75% alcohol-pickled sterilization, the aseptic tumor tissue of getting, the injection physiological saline that adds 5 times of volumes (W/V), grind to form homogenate with tissue homogenizer system, get tumor cell suspension with the 200 order stainless steel sift net filtrations of sterilizing.The same C57BL/6 mouse armpit that is inoculated in is subcutaneous, the conventional raising.
Grouping and administration: 50 of tumor-bearing mices, be divided into 5 groups at random by body weight, 10 every group, be respectively model group, endoxan group, ZONK088CT10,30,90mg/kg group.Each organizes mouse by dosage shown in the table 3 and mode administration, and the endoxan group only gives endoxan one time in the abdominal cavity in lotus knurl second day, and ZONK088CT organizes equal every day of tail intravenously administrable 1 time, continuous 10 days.Administration volume 20ml/kg body weight.After the last administration 24 hours, take off cervical vertebra and put to death mouse, weigh, strip tumor tissue and weigh, calculate tumour inhibiting rate.
The result with
Expression is organized a significant difference relatively with the t check.
The result shows, the ZONK088CT continuous intravenous injection of 30mg/kg 10 days is inhibited to the melanomatous growth of mice transplanted tumor B16.
Table 2 ZONK088CT is to the restraining effect of mouse B16 melanoma growth
Compare with model group:
*, P＜0.05;
*, P＜0.01.
Commercial Application
Compound 6 and analog formula (I) compound thereof are a kind of new polyamine compounds, have good antitumor activity and lower toxicity. Compound 6 and salt compound 1 thereof might become new antineoplastic, the present invention is the selective inhibition tumor cell of preparation, the polyamine compounds little to body toxicity lays a solid foundation, and has important hidden industry and melts the value of making an offer, to the major contribution of human research's cancer therapy drug. Preparation method's materials safety provided by the invention, equipment is simple, production method is simple, has good market prospects.
Claims (6)
1. formula (I) compound or its pharmacy acceptable salt:
R＝-CH
2CF
3；-CH
2CH
2F；-CH
2Cl；-CH
2CH
2Cl；CH
2CH
2Br；-CF
3；-CH
2Br。
Described pharmacy acceptable salt can be inorganic salt and organic salt, example hydrochloric acid salt, phosphoric acid salt salt, vitriol, acetate, oxalate, malate etc.
2. compound as claimed in claim 1 or its pharmacy acceptable salt is characterized in that: R=-CH
2CF
3
3. pharmacy acceptable salt as claimed in claim 2 is characterized in that: described salt is hydrochloride, is preferably 4HCl salt.
4. the described formula of claim 1 (I) compound or its pharmacy acceptable salt prevent and/or treat application in the tumour medicine in preparation.
5. application as claimed in claim 8 is characterized in that: described tumour is liver cancer or lung cancer.
6. use as claimed in claim 8 or 9, it is characterized in that: the described formulation that prevents and/or treats tumour medicine is injection liquid, lyophilized powder, oral tablet, capsule, dripping pill or granule.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100793917A CN102212013A (en) | 2011-03-30 | 2011-03-30 | Polyamine compound and preparation method and application thereof |
| PCT/CN2011/076553 WO2012129859A1 (en) | 2011-03-30 | 2011-06-29 | Polyamine compounds and preparative mentods and uses thereof |
| CN201180068382.6A CN103502201A (en) | 2011-03-30 | 2011-06-29 | Polyamine compounds and preparative methods and uses thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100793917A CN102212013A (en) | 2011-03-30 | 2011-03-30 | Polyamine compound and preparation method and application thereof |
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|---|---|
| CN102212013A true CN102212013A (en) | 2011-10-12 |
Family
ID=44743583
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| CN2011100793917A Pending CN102212013A (en) | 2011-03-30 | 2011-03-30 | Polyamine compound and preparation method and application thereof |
| CN201180068382.6A Pending CN103502201A (en) | 2011-03-30 | 2011-06-29 | Polyamine compounds and preparative methods and uses thereof |
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| WO (1) | WO2012129859A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104072624A (en) * | 2014-05-15 | 2014-10-01 | 温州医科大学 | Polyamine modified polymer drug as well as preparation method and application thereof as anti-tumor drug |
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| CN1121707A (en) * | 1993-12-27 | 1996-05-01 | 西巴-盖尔基股份公司 | Unsaturate amino compounds for use as anticancer and antiprotozoic agent |
| WO1998017624A1 (en) * | 1996-10-18 | 1998-04-30 | Wisconsin Alumni Research Foundation | Conformationally restricted polyamines and their use as antineoplastic agents |
| WO2007106554A2 (en) * | 2006-03-14 | 2007-09-20 | Progen Pharmaceuticals, Inc. | Treatment and prevention of vascular hyperplasia using polyamine and polyamine analog compounds |
| WO2009055823A2 (en) * | 2007-10-26 | 2009-04-30 | Progen Pharmaceuticals Limited | Method to predict responsiveness of breast cancer to polyaminetype chemotherapy |
-
2011
- 2011-03-30 CN CN2011100793917A patent/CN102212013A/en active Pending
- 2011-06-29 CN CN201180068382.6A patent/CN103502201A/en active Pending
- 2011-06-29 WO PCT/CN2011/076553 patent/WO2012129859A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1121707A (en) * | 1993-12-27 | 1996-05-01 | 西巴-盖尔基股份公司 | Unsaturate amino compounds for use as anticancer and antiprotozoic agent |
| WO1998017624A1 (en) * | 1996-10-18 | 1998-04-30 | Wisconsin Alumni Research Foundation | Conformationally restricted polyamines and their use as antineoplastic agents |
| WO2007106554A2 (en) * | 2006-03-14 | 2007-09-20 | Progen Pharmaceuticals, Inc. | Treatment and prevention of vascular hyperplasia using polyamine and polyamine analog compounds |
| WO2009055823A2 (en) * | 2007-10-26 | 2009-04-30 | Progen Pharmaceuticals Limited | Method to predict responsiveness of breast cancer to polyaminetype chemotherapy |
Non-Patent Citations (5)
| Title |
|---|
| 《Antimicrobial Agents and Chemotherapy》 20070430 Yarlett, Nigel 等 Activities of DL-alpha-difluoromethylarginine and polyamine analogues against Cryptosporidium parvum infection in a T-cell receptor alpha-deficient mouse model 第1235页 1-6 第51卷, 第4期 * |
| CARRUTHERS, LENNY M 等: "Polyamine analogues: potent inducers of nucleosomal array oligomerization and inhibitors of yeast cell growth", 《BIOCHEMICAL JOURNAL 》 * |
| LOUSSOUARN, G 等: "Molecular basis of inward rectification: Structural features of the blocker defined by extended polyamine analogs", 《MOLECULAR PHARMACOLOGY》 * |
| YARLETT, NIGEL 等: "Activities of DL-α-difluoromethylarginine and polyamine analogues against Cryptosporidium parvum infection in a T-cell receptor alpha-deficient mouse model", 《ANTIMICROBIAL AGENTS AND CHEMOTHERAPY》 * |
| 任玉珊 等: "多胺类似物及其抗肿瘤作用机制", 《中国新药与临床杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104072624A (en) * | 2014-05-15 | 2014-10-01 | 温州医科大学 | Polyamine modified polymer drug as well as preparation method and application thereof as anti-tumor drug |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2012129859A1 (en) | 2012-10-04 |
| CN103502201A (en) | 2014-01-08 |
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Application publication date: 20111012 |